Project 3: Imaging neurotoxicity: The effect of anti-NMDAR Ab on hippocampus and amygdala in NPSLE patients (Hirsch, PI) Systemic lupus erythematosus is an autoimmune disease characterized by the presence of anti-nuclear antibodies, especially antibodies to DNA. Patients with lupus develop, over time, cognitive impairment and mood disorders. We have identified a subset of anti-DNA antibodies that cross-reacts with the NR2A and NR2B subunits of the NMDA receptor (NMDAR). In mice, antibodies with this crossreactivity can cause apoptosis of neurons in the hippocampus or the amygdala, leading to cognitive impairment or behavioral dysfunction, respectively. We hypothesize that antibody, together with a breach in the blood-brain barrier, can damage the hippocampus and amygdala in lupus patients, and that insults that open the blood-brain barrier accumulate over time. This project is designed to assess whether functional Magnetic Resonance Imagining (fMRI) is a sensitive modality to assess cognitive function and emotional response in patients with SLE and whether the subset of anti-DNA antibodies that cross-reacts with the NMDAR associates with impairment. We will determine whether patients with anti-NMDAR antibodies acquire impairment over time using fMRI to assess activity in the hippocampus and the amygdala, regions subserving cognition and emotional memory. Two studies are proposed: a cohort analysis to determine whether antibody associates with impairment in patients with disease for 10 or more years, and whether antibody associates with early impairment in patients with disease for less than 2 years. The second study is a longitudinal assessment of patients to determine if fMRI can detect change over a 6 month time interval. This study is a necessary precondition to a clinical trial of neuroprotection in SLE.